Increased selectivity of anti-cancer agents is an important factor in designing new drugs for the treatment of cancer. The design and synthesis of novel compounds that can be activated selectively in cancer cells is therefore an attractive way to target the inhibition of tumor growth. This strategy ensures that cytotoxicity occurs selectively in malignant cells and might lead to a reduction of many of the side effects commonly caused by chemotherapeutic agents currently in use. An approach to the enhancement of selectivity for cytotoxic chemotherapy involves the design of prodrugs that undergo preferential activation by enzymes that are overexpressed in tumors. These prodrugs, which are not cytotoxic until they are metabolically activated, can serve to deliver selectively the cytotoxic agent to the tumor site.
One such prodrug that is used clinically is the compound cyclophosphamide (1, FIG. 1). Cyclophosphamide is activated to 4-hydroxycyclophosphamide (1a) by hepatic cytochrome P-450 oxidation (FIG. 1). Subsequent β-elimination from the aldehyde tautomer of 1a releases phosphoramide mustard 2 as the active drug which can cyclize intramolecularly to a short-lived electrophilic aziridinium ion intermediate (3). Nucleophilic addition can then occur and the cyclization/addition process can be repeated. Ultimately, if DNA is the nucleophile, the phosphoramide mustard can cross-link DNA and inhibit further DNA replication, a process that leads to cell death.
The design of chemotherapeutic quinone prodrugs that are bioreductively activated by the enzyme DT-diaphorase has also been investigated (see for example P. Workman, Oncol. Res., 1994, 6,461–475; and R. J. Riley and P. Workman, Biochem. Pharmacol., 1992, 43, 1657–1669). Many of the compounds studied include benzimidazolequinone, benzoquinone and naphthoquinone prodrugs, with and without an alkylating moiety attached to the core ring structure, and indolequinone analogs patterned after the known cytotoxic agents Mitomycin C and E09. Sartorelli et al prepared a series of naphthoquinone prodrugs that could potentially be transformed into alkylating moieties following the expulsion of a leaving group from the bioreductively activated compound (see for example, N. E. Sladek, Pharmac. Ther., 1988, 37, 301–355; and M. Colvin et al., Cancer Res., 1976, 36, 1121–1126).
Despite the reported success in treating cancer with the compound Cyclophosphamide, there is currently a need for structurally novel therapeutic agents that can be used to treat cancer.